The long-term goal of this project is to identify and study the factors that regulate how maternal diabetes mellitus during pregnancy affects maternal, placental and fetal metabolism and fetal growth. This project will be carried out with three major objectives: 1) induce a diabetic state by mid-gestation in pregnant ewes in order to measure the long-term consequences of maternal hyperglycemia throughout the latter half of pregnancy on maternal glucose metabolism and on placental and fetal glucose, lactate amino acid and oxygen metabolism; 2) distinguish the role of the placenta from fetal factors in regulating fetal metabolism in relation to maternal hyperglycemia; 3) measure the long-term (several weeks) effects of selective changes of fetal insulin and glucose concentrations on fetal glucose, lactate, amino acid and oxygen metabolism. The maternal-placental-fetal metabolism and metabolic exchange will be quantified using techniques of umbilical and uterine blood flow measurement, chemical analyses of maternal arterial, uterine venous, umbilical arterial, and umbilical venous blood, tracer methodology, and glucose clamp methodology. These studies are important to diabetes mellitus in several respects: 1) these studies are unique in their ability to quantify metabolism in the mother, placenta and fetus simultaneously; 2) this ability will provide important information about how spontaneous and therapeutically induced changes in maternal glucose homeostasis affect both placental and fetal metabolism; 3) these studies will extend previous work from short term, several-hours observations to chronic, several-week observations, allowing for the first time a sequential analysis of maternal, placental and fetal metabolism during a diabetic pregnancy; 4) these studies will address directly the control of placental and fetal oxidative metabolism, in order to observe how chronic maternal hyperglycemia may produce fetal hypoxemia and lead potentially to selected fetal morbidities as well as mortality; 5) these studies are also important for establishing an original approach to measuring the effects of oxidative substrates and insulin levels on fetal amino acid metabolism, developing for the first time an in vivo approach to studying the integration of substrate and hormonal effects on fetal oxidative metabolism and fetal growth.